Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

abstract = "We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors{\textquoteright} tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.",

author = "Campbell, {Brittany B.} and Nicholas Light and David Fabrizio and Matthew Zatzman and Fabio Fuligni and {de Borja}, Richard and Scott Davidson and Melissa Edwards and Elvin, {Julia A.} and Hodel, {Karl P.} and Zahurancik, {Walter J.} and Zucai Suo and Tatiana Lipman and Katharina Wimmer and Kratz, {Christian P.} and Bowers, {Daniel C.} and Laetsch, {Theodore W.} and Dunn, {Gavin P.} and Johanns, {Tanner M.} and Grimmer, {Matthew R.} and Smirnov, {Ivan V.} and Val{\'e}rie Larouche and David Samuel and Annika Bronsema and Michael Osborn and Duncan Stearns and Pichai Raman and Cole, {Kristina A.} and Storm, {Phillip B.} and Michal Yalon and Enrico Opocher and Gary Mason and Thomas, {Gregory A.} and Magnus Sabel and Ben George and Ziegler, {David S.} and Scott Lindhorst and Issai, {Vanan Magimairajan} and Shlomi Constantini and Helen Toledano and Ronit Elhasid and Roula Farah and Rina Dvir and Peter Dirks and Annie Huang and Galati, {Melissa A.} and Jiil Chung and Vijay Ramaswamy and Irwin, {Meredith S.} and Melyssa Aronson and Carol Durno and Taylor, {Michael D.} and Gideon Rechavi and Maris, {John M.} and Eric Bouffet and Cynthia Hawkins and Costello, {Joseph F.} and Meyn, {M. Stephen} and Pursell, {Zachary F.} and David Malkin and Uri Tabori and Adam Shlien",

year = "2017",

month = nov,

day = "16",

doi = "10.1016/j.cell.2017.09.048",

language = "English (US)",

volume = "171",

pages = "1042--1056.e10",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Comprehensive Analysis of Hypermutation in Human Cancer

AU - Campbell, Brittany B.

AU - Light, Nicholas

AU - Fabrizio, David

AU - Zatzman, Matthew

AU - Fuligni, Fabio

AU - de Borja, Richard

AU - Davidson, Scott

AU - Edwards, Melissa

AU - Elvin, Julia A.

AU - Hodel, Karl P.

AU - Zahurancik, Walter J.

AU - Suo, Zucai

AU - Lipman, Tatiana

AU - Wimmer, Katharina

AU - Kratz, Christian P.

AU - Bowers, Daniel C.

AU - Laetsch, Theodore W.

AU - Dunn, Gavin P.

AU - Johanns, Tanner M.

AU - Grimmer, Matthew R.

AU - Smirnov, Ivan V.

AU - Larouche, Valérie

AU - Samuel, David

AU - Bronsema, Annika

AU - Osborn, Michael

AU - Stearns, Duncan

AU - Raman, Pichai

AU - Cole, Kristina A.

AU - Storm, Phillip B.

AU - Yalon, Michal

AU - Opocher, Enrico

AU - Mason, Gary

AU - Thomas, Gregory A.

AU - Sabel, Magnus

AU - George, Ben

AU - Ziegler, David S.

AU - Lindhorst, Scott

AU - Issai, Vanan Magimairajan

AU - Constantini, Shlomi

AU - Toledano, Helen

AU - Elhasid, Ronit

AU - Farah, Roula

AU - Dvir, Rina

AU - Dirks, Peter

AU - Huang, Annie

AU - Galati, Melissa A.

AU - Chung, Jiil

AU - Ramaswamy, Vijay

AU - Irwin, Meredith S.

AU - Aronson, Melyssa

AU - Durno, Carol

AU - Taylor, Michael D.

AU - Rechavi, Gideon

AU - Maris, John M.

AU - Bouffet, Eric

AU - Hawkins, Cynthia

AU - Costello, Joseph F.

AU - Meyn, M. Stephen

AU - Pursell, Zachary F.

AU - Malkin, David

AU - Tabori, Uri

AU - Shlien, Adam

PY - 2017/11/16

Y1 - 2017/11/16

N2 - We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

AB - We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.